1. Field of the Invention
The present invention relates to new modulators of dopamine neurotransmission, and more specifically to new 4-(ortho, meta disubstituted phenyl)-1-alkylpiperidines and piperazines, and use thereof.
2. Description of Prior Art
Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous functions (e.g. regulation of appetite, body temperature, sleep). Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, drugs that act, directly or indirectly at central dopamine receptors are commonly used in the treatment of neurological and psychiatric disorders, e.g. Parkinson's disease and schizophrenia. However, currently available dopaminergic pharmaceuticals can have severe side effects. For instance, dopamine antagonists are known to induce both motor (extrapyramidal side effects; EPS) and mental side effects (e.g. anhedonia, dysphoria, and impairment of cognition), and dopaminergic agonists are known to induce dyskinesias and psychoses (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed./McGraw-Hill, USA. Chapter 18, p 407-416, Chapter 22, p 509-512, p 515-516). An approach adopted by many researchers to improve efficacy and reduce side effects of dopaminergic pharmaceuticals, is to develop novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or with regional selectivity. Yet another class of compounds acting through the dopamine systems of the brain are dopaminergic stabilizers, which have shown to be useful in the treatment of both neurologic and psychiatric disorders (A. Ekesbo, PhD Thesis, Uppsala University, Sweden: Functional consequences of dopaminergic degeneration; clinical and experimental studies using a novel stabilizer of dopaminergic systems: Ekesbo et al, (−)-OSU6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson's disease, Neuroreport, 8, 2567, 1997; Tedroff et al. Long-lasting improvement in motor function following (−)-OSU6162 in a patient with Huntington's disease. Neurology, 22; 53:1605-6, 1999; Gefvert O. et al, (−)-OSU6162 induces a rapid onset of antipsychotic effect after a single dose. A double-blind placebo-controlled pilot study. Scandinavian Society for Psychopharmacology, 41st Annual Meeting, Copenhagen Denmark Nordic Journal of Psychiatry 54/2 93-94, April 2000: Carlsson et al, Annu. Rev. Pharmacol. Toxicol., 41, 237, 2001; Carlsson et al. Current Medicinal Chemistry, 11, 267, 2004).
Another dopaminergic compound, which has been referred to as a dopamine-serotonin system stabiliser, as well as a partial DA D2 receptor agonist, is the recently-launched antipsychotic compound aripiprazole (Burris et al, Pharm. Exp. Ther, vol. 302, 381, 2002.). Furthermore, compounds referred to as dopaminergic stabilizers have been described in WO01/46145, WO01/46146, Pettersson et al. The development of ACR16. A new class of dopaminergic stabilizers. Society for Neuroscience 32nd Annual Meeting, Abstract 2002, Vol. 28 part 1 1028, Orlando USA 2002, and Nyberg et al Efficacy and tolerability of the new dopamine stabiliser ACR16 a randomised placebo-controlled add-on study in patients with schizophrenia 12th BIENNIAL WINTER WORKSHOP ON SCHIZOPHRENIA, 7-13 Feb. 2004, Davos, Switzerland.
The typical pharmacological effects which are characteristic for dopaminergic stabilizers as described in WO01/46145, WO01/46146 and Pettersson et al. 2002 can be summarised as: 1) Increased turnover of dopamine in the terminal areas of the ascending dopaminergic projections of the mammalian brain; 2) No or only weak behavioural effects in otherwise untreated rats; and 3) Inhibition of behavioural effects induced by psychostimulants or psychotomimetic compounds in the rat. In the present invention this is referred to as a dopaminergic stabilizer profile.
This invention relates to the field of treatment of mammals suffering from CNS disorders in which the symptoms can be affected by dopaminergic functions, where the treatment comprises administering to said mammal an amount of a new type of compound, with a dopaminergic stabilizer profile.
Compounds belonging to the class of substituted 4-phenyl-N-alkyl piperidines have been reported previously. Among these compounds, some are inactive in the CNS, some display serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.
Costall et al. European J. Pharm. 31, 94, (1975) and Mewshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998) report compounds which are substituted 4-phenyl-piperazines, most of them being 2-, 3- or 4-OH phenyl substituted and displaying DA autoreceptor agonist properties. Fuller R. W. et al, J. Pharmacol. Exp. Therapeut. 218, 636, (1981) disclose substituted piperazines (e.g. 1-(m-trifluoro-methylphenyl)piperazine) which reportedly act as serotonin agonists and inhibit serotonin re-uptake. The comparative effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1-(p-chlorophenol)-piperazine are disclosed by Fuller R. W. et al, Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980). Fuller R. W. et al, Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3,4-dihydroxy-phenylacetic acid concentration in rat brain by 1-(p-chlorophenol)-piperazine.
Boissier J. et al Chem Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives, potentiators of barbiturates, and depressants of the central nervous system.
A number of differently substituted piperazines have been published as ligands at 5-HT 1A receptors, for example Glennon R. A. et al J. Med. Chem., 31, 1968, (1988), Mokrosz, J. et al Arch. Pharm. (Weinheim) 328, 143-148 (1995), and van Steen B. J., J. Med. Chem., 36, 2751, (1993), Dukat M.-L., J. Med. Chem., 39, 4017, (1996).
GB2027703 discloses substituted phenyl piperazines as analgesics and psychotropic agents. GB1560271 discloses para-substituted meta-trifluoromethylphenyl piperazines and their therapeutic use in CNS and cardiovascular disorders. U.S. Pat. No. 4,202,898 discloses substituted phenylpiperazines for the treatment of anxiety and depression. U.S. Pat. No. 3,326,916 discloses different N-alkyl substituted 4-(3-trifluoromethyl-phenyl)-piperazines for the treatment of anxiety and related psychiatric conditions. WO9811068 discloses substituted piperazines as selective dopamine D4 ligands to be used in the treatment of anxiety, de-pression, schizophrenia, obsessive ideas, Parkinson's disease, tardive dyskinesia, nausea and gastro-intestinal tract disorders.
A number of 4-phenylpiperidine derivatives are known. EP0369887 disclose substituted 4-(meta-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines for treatment of anxiety. WO00/03713 discloses a method for the treatment of schizophrenia and other dopamine system dysfunctions by using substituted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridines.
Glennon et al. (U.S. Pat. No. 6,057,371) claim a method for treating sigma receptor associated CNS disorder, comprising the administration of arylamines, including arylpiperidines, which are either unsubstituted or mono-substituted at the aryl ring. The compounds exhibit a high binding affinity with respect to the sigma receptor. WO 91/095954 states that the term “high affinity” is intended to mean a compound which exhibits an IC50 of less than 100 nM in the assay against 3H-DTG described in Weber et al. Proc. Natl. Acad. Sci. (USA) 83: 8784-8788). Specifically, WO 91/095954 discloses compositions relating to “the discovery that certain phenylalkyl-amine, aminotetraline, piperazine, piperidine and related derivatives have high binding to the sigma receptor and unexpectedly low binding for the PCP and DA receptors” (see page 11, lines 33-36).
WO 91/095954 and WO 93/00313 both require that the compounds have a high binding affinity to the sigma receptor and do not disclose that the compounds are pharmacologically active in the absence of sigma receptor affinity. In addition, clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evidence of antipsychotic activity, nor activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (Rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al, 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al, 1994, Neuropsychopharmacology 10:37-40).
U.S. Pat. No. 4,415,736 discloses 4-(2,3-dimethoxy-phenyl)-1-methyl-4-piperidinol (col. 9 lines 18-19) as a synthesis intermediate
In addition, it is known that compounds with formulae II (WO01/46145) and III (WO01/46146) possess dopaminergic stabilizer properties.

In formula II;
X is, inter alia, CH, R1 is selected from the group consisting of OSO2CF3, OSO2CH3, SOR3, SO2R3, CORS, CN, NO2, CONHR3, CF3 (proviso X is CH or C) F, Cl, Br, I (wherein R3 is as specified below);
R2 is selected from the group consisting of C1-C4 alkyl, allyl, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or —(CH2)—R4 (wherein R4 is as specified below);
R3 is selected from the group consisting of C1-C3 alkyl, CF3, or N(R2)2;
R4 is selected from the group consisting of C3-C6 cycloalkyl, 2-tetrahydrofurane, 3-tetra-hydrofuran.
In formula III;
X is, inter alia, CH, R1 is selected from the group consisting of OSO2CF3, OSO2CH3, SOR7, SO2R7, COR7, CN, NO2, CONHR3, CF3, F, Cl, Br, I (wherein R3 is as specified below), 3-thiophene, 2-thiophene, 3-furane, 2-furane;
R2 is selected from the group consisting of F, Cl, Br, I, CN, CF3, CH3, OCH3, OH, NH2 
R3 and R4 are independently H or C1-C4 alkyl
R5 is selected from the group consisting of C1-C4 alkyl, allyl, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or —(CH2)—R6;
R6 is selected from the group consisting of C3-C6 cycloalkyl, 2-tetrahydrofurane, 3-tetrahydrofurane.
R7 is selected from the group consisting of C1-C3 alkyl, CF3 or N(R4)2 
However, WO01/46145 (Formula II) only discloses mono-substitution of the aryl ring, and does not exemplify ortho-substitution. WO01/46146 does not disclose 2,3-disubstitution of the aryl ring, and it can be seen that alternative substitution patterns (e.g. 3,4-disubstitution in which the 4-position is halogen) are not as potent as the 2.3-disubstitution disclosed in the present invention.